Project Summary/Abstract Regulation of RNA biogenesis and decay is critical for cellular homeostasis and dysregulation in these processes leads to a variety of human developmental and metabolic disorders. While the transcriptional regulation of RNA expression has been widely studied, the importance of RNA decay is only beginning to be appreciated. Specifically, studying the regulation of noncoding RNA (ncRNA) expression and decay is hampered due to limitations caused by their size, abundance, modifications, and/or structural complexities. We have recently identified a 3?-to-5? exoribonuclease enzyme, Dis3l2, as a major player in ncRNA decay. In that study, I performed a global identification of Dis3l2 substrates and found that the majority of Dis3l2 targets are ncRNAs. This led to our identification of DIS3L2-Mediated Decay (DMD) as a quality control pathway that ensures the fidelity of ncRNAs. Germline mutations in human DIS3L2 gene have been linked to the Perlman syndrome that is a rare but devastating disorder associated with early lethality, hypoglycemia, kidney abnormalities, and hyperplasia in pancreas. These suggest that dysregulated ncRNA decay in Dis3l2-depleted patients disrupts metabolic homeostasis. The main aim of this research project is to unravel how Dis3l2 deficiency leads to the impaired function of metabolic organs remains unknown. To understand the role of ncRNA decay in metabolism and specially in glucose homeostasis, I plan to combine several innovative approaches to investigate the molecular and physiological functions of Dis3l2 enzyme using in vitro and in vivo systems. I have identified the 7SL RNA component of the signal recognition particle (SRP), a critical player in endoplasmic reticulum (ER)-mediated translation, as a major substrate of Dis3l2. I discovered that in the absence of Dis3l2, aberrant 7SL RNAs accumulate in the cells and perturb ER-mediated protein translation. We have generated a Dis3l2 knockout (KO) mouse model of Perlman syndrome that manifests the main symptoms of human patients including perinatal lethality, kidney overgrowth, abrogated regulation of blood glucose and insulin secretion. Moreover, Dis3l2 depletion caused impaired ER-translation, ER-calcium homeostasis and insulin secretion in vitro. This proves a direct role of Dis3l2 in regulation of insulin secretion in response to glucose stimulation. I will utilize Dis3l2 KO mouse model to further determine the effect of impaired ER-mediated protein translation on cellular and organism physiology. My hypothesis is that Dis3l2 depletion impairs homeostatic ER-associated protein translation due to an accumulation of aberrant 7SL RNAs. This proposal is innovative because the involvement of the Dis3l2-mediated ncRNA decay in glucose homeostasis has not been previously reported. Successful completion of this proposal has broad implications in understanding the basis of glucose homeostasis and have a significant impact on the development of treatments for diabetes.